SHANK3 – Phelan-McDermid Syndrome

SHANK3, encoded by SHANK3, is a scaffold protein localized to the postsynaptic density of excitatory synapses. Haploinsufficiency of SHANK3 due to terminal 22q13 deletions or intragenic loss-of-function variants causes Phelan-McDermid syndrome, a contiguous gene disorder characterized by global developmental delay, hypotonia, absent or severely delayed speech, intellectual disability, and autism spectrum features (PMID:12920066).

Genetic Evidence

SHANK3-related Phelan-McDermid syndrome follows an autosomal dominant inheritance with de novo occurrence in the vast majority of cases. Over 600 individuals have been reported with terminal 22q13 deletions encompassing SHANK3 (PMID:22670140), and at least 21 patients harbor intragenic SHANK3 point mutations or small deletions (PMID:35495150). A representative pathogenic variant is c.5253G>A (p.Trp1751Ter) (PMID:26045941), which introduces a premature stop codon in exon 21 of SHANK3 and disrupts the sterile alpha motif domain.

Genotype–phenotype correlation studies demonstrate that larger deletions often correlate with more severe dysmorphic features, renal anomalies, and motor deficits, whereas SHANK3-only mutations chiefly affect neurodevelopmental outcomes such as speech and cognitive function (PMID:33949759). Familial segregation is rare, reflecting the de novo origin of most SHANK3 disruptions.

Functional Evidence

Mouse models with Shank3 knockout recapitulate core neurological features of Phelan-McDermid syndrome, including impaired synaptic plasticity, reduced striatal NMDA/AMPA ratios, and abnormal social and repetitive behaviors (PMID:27021819, PMID:26559786). Human neurons derived from SHANK3-deficient iPSCs exhibit reduced neurite outgrowth, smaller growth cones, and deficient excitatory synaptic transmission, confirming a cell-autonomous role for SHANK3 in neurodevelopment (PMID:30918484).

Mechanistic studies reveal that SHANK3 interacts with metabotropic glutamate receptor 5 (mGluR5) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels to regulate synaptic strength and Ih currents. Augmentation of mGluR5 activity rescues synaptic and behavioral deficits in Shank3Δ1–/– mice (PMID:27021819), while Ih channelopathy underlies neuronal hypoexcitability in SHANK3 mutant human neurons (PMID:26966193).

Dietary zinc supplementation in Shank3 exon 13–16 mutant mice restores SHANK2 recruitment, normalizes NMDA receptor function, and alleviates repetitive behaviors (PMID:30405356). Similarly, oxytocin administration ameliorates social memory deficits and synaptic plasticity impairments in a Shank3-deficient rat model (PMID:28139198).

Integration & Clinical Utility

The cumulative genetic and functional data firmly establish SHANK3 haploinsufficiency as the molecular basis for Phelan-McDermid syndrome, meeting ClinGen criteria for a Definitive gene–disease association. Genetic testing should include chromosomal microarray for 22q13 deletions and sequencing of SHANK3 to detect point mutations. Functional assays in model systems have identified potential therapeutic targets—mGluR5 modulation, zinc supplementation, and oxytocin—that warrant clinical evaluation. Key Take-home: SHANK3 haploinsufficiency drives neurodevelopmental deficits in Phelan-McDermid syndrome, and targeted synaptic modulation offers a promising avenue for precision therapies.

References

• Journal of medical genetics • 2003 • Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. PMID:12920066
• Molecular syndromology • 2012 • The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). PMID:22670140
• Molecular autism • 2015 • Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. PMID:26045941
• Molecular psychiatry • 2017 • Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. PMID:27021819
• Science • 2016 • Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. PMID:26966193
• Molecular autism • 2019 • Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons. PMID:30918484
• Frontiers in cellular neuroscience • 2018 • Dietary Zinc Supplementation Prevents Autism Related Behaviors and Striatal Synaptic Dysfunction in Shank3 Exon 13-16 Mutant Mice. PMID:30405356
• eLife • 2017 • Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. PMID:28139198

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